Cytochalasins interfere with cytokinesis, growth of rat tumors, nucleoside and glucose transport by rat hepatoma cells, calcium transport and other cell membrane, microtubule, and microfilament functions. Cyto B induces multinucleation of cultured human cancer cells at a dosage which causes binucleation of normal cells. Cyto D (11-membered carbocycle) is more active than cyto B (14-membered lactone) and must retain the macrocycle for high activity. Our goal is synthesis of cytotoxic cyto D analogs by new and general methods of multi-carbon ring expansion. The strategy involves stereospecific synthesis of the bicyclic lactam subunit. The macrocycle is then "grown" by a repeatable sequence of sigmatropic shifts to provide easy access to carbocyclic analogs of 5 or more members, or heterocyclic analogs of 6 or more members. Macroheterocycles influence cation transport at cell membranes by chelation. Holley (1972) has related malignant growth to abnormal membrane transport properties. Since cytochalasins affect nutrient transport, and act more dramatically on malignant than on normal cells, it is plausible that chelation phenomena are involved in cytotoxicity. Synthetic routes to cyto analogs containing sulfur or nitrogen in the macrocycle are proposed to test the role of chelation. The results will establish the optimum ring size and substitution for cytotoxicity, and may clarify the mode of cytochalasin interaction with tumor cell membranes.